Adverse antibiotic effects associated with renal insufficiency.

We review the English-language literature on antibiotic-associated adverse reactions in patients with renal insufficiency in order to highlight this important but often overlooked clinical problem. Because many adverse reactions to antibiotics are not dependent on renal function, we have attempted to review only those reactions that are believed to be associated with renal insufficiency or that have been reported in patients with impaired renal function. Adverse effects of antibiotics in this setting can be divided into six major categories: neurologic toxicity, coagulopathy, nephrotoxicity, hypoglycemia, hematologic toxicity, and aminoglycoside inactivation by penicillins. Neurologic toxicity can be further divided into central nervous system toxicity consisting primarily of encephalopathy and seizures, ototoxicity, peripheral neuropathy, and neuromuscular blockade/respiratory depression. We explore the factors in uremia that may contribute to the susceptibility of patients with renal insufficiency to the adverse effects of antibiotics. Moreover, we make general recommendations regarding the use of the discussed antibiotics in patients with compromised renal function.

Epidemiology of infections caused by gentamicin-resistant enterobacteriaceae and Pseudomonas aeruginosa over 15 years at the Nashville Veterans Administration Medical Center.

Nosocomial infections and gentamicin resistance were surveyed over 15 years at Nashville Veterans Administration Medical Center, and trends for Enterobacteriaceae and Pseudomonas aeruginosa were contrasted. Analysis of approximately 6,000 nosocomial infections indicated that four-fifths were caused by aerobic gram-negative bacilli. Three hospital-wide outbreaks caused by Enterobacteriaceae occurred; these three outbreaks were due to Serratia marcescens, Klebsiella pneumoniae, and Enterobacter cloacae, respectively. The outbreaks were temporally related to the emergence of gentamicin resistance. Detailed analysis of the recent outbreak due to Enterobacter indicated that an increasing prevalence of gentamicin-resistant E. cloacae predated nosocomial infections by several months; this pattern suggested that such outbreaks could be predicted. Molecular epidemiologic data pertaining to the preservation over a decade of genes encoding gentamicin resistance were reviewed. In contrast to Enterobacteriaceae, P. aeruginosa gradually and progressively developed resistance to gentamicin that spread in an endemic fashion, with parallel increases in nosocomial infections. This pattern appeared to relate to different modes of spread and persistence for resistant P. aeruginosa that may require unique methods for control.

Nosocomial infectious balanoposthitis in neutropenic patients.

We have reported balanoposthitis as a source of fever and bacteremia in two neutropenic uncircumcised patients. The etiologic organisms were Pseudomonas aeruginosa in one case and Providencia stuartii in the other. In one patient, the diagnosis was delayed by the presence of a condom catheter. This emphasizes the importance of personal hygiene in uncircumcised men about to undergo immunosuppressive therapy, and the need for judicious use of condom catheters in such patients.

Discrepancies between disk diffusion and broth susceptibility studies of the activity of ticarcillin plus clavulanic acid against ticarcillin-resistant Pseudomonas aeruginosa.

Ticarcillin and clavulanic acid in combination were tested against 40 Pseudomonas aeruginosa isolates resistant to ticarcillin by disk diffusion. A total of 21 isolates (53%) were susceptible to ticarcillin-clavulanate by disk diffusion, under currently recommended criteria for ticarcillin susceptibility. Macro-broth dilution tests (ticarcillin plus clavulanic acid, 2 micrograms/ml) confirmed susceptibility (MIC less than or equal to 64 micrograms/ml) of only 8 (38%) of 21 isolates. Time-kill studies of disk diffusion susceptible isolates indicated 2 log10 or greater killing of most isolates at 6 h in broth containing ticarcillin (64 micrograms/ml) combined with clavulanic acid (1, 2, 5, or 10 micrograms/ml). After 6 h, regrowth was common in all concentrations of clavulanic acid except 10 micrograms/ml. Regrowth populations were resistant to ticarcillin-clavulanate by MIC determination. Poor bactericidal activity of ticarcillin-clavulanate against ticarcillin-resistant P. aeruginosa was confirmed, as most isolates did not undergo 99.9% or greater killing at 24 h in all concentrations of clavulanic acid. Serotype O-11 was our most common serotype and was associated with disk diffusion "pseudosusceptibility." Concomitant disk diffusion testing of ticarcillin-clavulanate and ticarcillin is recommended for testing the susceptibility of P. aeruginosa to ticarcillin-clavulanate by disk diffusion. P. aeruginosa isolates resistant to ticarcillin should as a rule be considered also resistant to ticarcillin-clavulanate, despite apparent susceptibility by disk diffusion.

Ketoconazole's inhibition of fungal antigen-induced thymidine uptake by lymphocytes from patients with psoriasis.

Ketoconazole, an oral antifungal imidazole, has been effective in some refractory cases of psoriasis, particularly those with scalp involvement, perhaps because of suppression of Pityrosporum ovale. To assess an ancillary immunologically mediated role for ketoconazole, its effects were evaluated on psoriatic patients' lymphocyte function. Ketoconazole in vitro markedly inhibited Pityrosporum antigen-induced lymphocyte blastogenesis as indicated by impairment of cellular tritiated thymidine uptake. Ketoconazole likewise inhibited lymphocyte uptake of other pyrimidine nucleosides by both normal and psoriatic lymphocytes. Neither imidazole or an investigational triazole antifungal (Bay n7133) inhibited the uptake. Thus, ketoconazole potentially could affect psoriasis in seborrheic areas of skin by a direct antifungal action or indirectly by suppressing fungal antigen-induced lymphocyte-mediated immune responses affecting the skin.

Failure of chloramphenicol and cefotaxime therapy in Klebsiella meningitis: possible role of antibiotic antagonism.

We have described a patient with Klebsiella pneumoniae meningitis who was treated with cefotaxime and chloramphenicol concomitantly, and whose slow initial resolution and subsequent relapse plus in vitro evidence of antagonism of cefotaxime appear to indicate that chloramphenicol interfered with the activity of the cephalosporin. Thus, concomitant use of chloramphenicol should probably be avoided or used advisedly in adults with gram-negative bacillary meningitis susceptible to a third generation cephalosporin.

Perirectal and perineal infections in end-stage renal disease patients.

Eight patients with end-stage renal disease (ESRD) who developed bacterial infection of the perirectal area or perineum are reported. The diagnosis was not always straightforward. Bacteremia was seen in 3 of 8 patients and one of these died. Careful examination of the anus, rectum, and perineum should be mandatory in ESRD patients with undiagnosed fever. Treatment consisted of extensive surgical debridement and drainage along with antimicrobial therapy.

Antagonism by chloramphenicol of broad-spectrum beta-lactam antibiotics against Klebsiella pneumoniae.

Chloramphenicol combined with cefotaxime, moxalactam, cefoperazone, aztreonam, or imipenem was tested in vitro against clinical isolates of Klebsiella pneumoniae. By time-kill cultures (killing curves), chloramphenicol interfered with activity of all five beta-lactams. When chloramphenicol was added before the beta-lactams, the action of cefotaxime, moxalactam, or cefoperazone against all isolates was antagonized at all times tested. The action of aztreonam was antagonized against four of six isolates. With imipenem, antagonism occurred against half of the isolates at some time during 24 h when chloramphenicol was added simultaneously, provided that a sufficient inoculum of K. pneumoniae was employed. Generally, less antagonism resulted when chloramphenicol was added after the cephalosporins. Interference of bactericidal activity of three new cephalosporins by chloramphenicol has potential clinical relevance to the therapy of gram-negative bacillary meningitis. The lesser antagonism of aztreonam and imipenem by chloramphenicol is of uncertain clinical relevance but indicates that this in vitro phenomenon may apply to a wide range of beta-lactam antibiotics.

Comparison of ketoconazole and amphotericin B in interference with thymidine uptake by and blastogenesis of lymphocytes stimulated with Histoplasma capsulatum antigens.

Human peripheral blood lymphocytes stimulated with Histoplasma capsulatum yeasts were exposed in culture to graded concentrations of ketoconazole or amphotericin B and subsequently assessed for membrane integrity, thymidine uptake, and blastogenesis. Lymphocyte reactivity varied with concentration and duration of exposure to ketoconazole. Overt membrane toxicity resulted from exposure to 40 micrograms of ketoconazole per ml for 5 days, diminished thymidine uptake occurred with concentrations as low as 5 micrograms/ml, and 15 to 20 micrograms/ml caused a marked decrease in thymidine uptake and eventually diminished blastogenesis. The antilymphocyte action of ketoconazole was neutralized by increasing the concentration of human serum in cultures to 40% regardless of its cholesterol content. Amphotericin B activity was qualitatively similar but less pronounced.

Nosocomial spread of Clostridium difficile.

Environmental transmission of Clostridium difficile, the causative agent of antibiotic-associated pseudomembranous colitis (PMC), has been supported by animal studies and implicated in spread of C. difficile among leukemic children receiving non-absorbable antibiotics. We report antibiotic-associated C. difficile-related colitis in two adults who shared a commode chair during hospitalization.

Histoplasma infection of abdominal aortic aneurysms.

Fungal endarteritis resulting from progressive disseminated histoplasmosis may cause arterial aneurysms, or lead to infection of pre-existing aneurysms. Three patients with Histoplasma capsulatum infections of abdominal aortic aneurysms are reported. All had previous disseminated histoplasmosis and atherosclerotic peripheral vascular disease. All were considered cured of systemic infection when their aneurysms were discovered. Atherosclerotic vascular lesions may become infected during the course of systemic fungal disease and may serve as a haven for viable organisms in patients whose dissemination recurs despite seemingly adequate antifungal therapy. In treating these patients, resection of all infected arterial tissue, revascularization through uninfected tissues, and long-term antimicrobial therapy are recommended.

Conditions associated with relapse of amphotericin B-treated disseminated histoplasmosis.

Progressive disseminated histoplasmosis (PDH) is a rare consequence of infection with Histoplasmia capsulatum. Usually fatal if untreated, PDH generally is cured by appropriate amphotericin B treatment. Of 31 persons with uncomplicated PDH treated with amphotericin B, we found that relapse occurred in five (16%) after an interval of up to nine years after initial therapy. Review of these five cases and 31 additional relapsing cases from the literature indicates that fungal endocarditis or endarteritis without surgical treatment, underlying lymphoreticular neoplasm, and amphotericin B dosage of less than 2 g appear to be associated with relapse of PDH.

Superior activity of N-formimidoyl thienamycin against gentamicin-resistant Pseudomonas aeruginosa.

N-Formimidoyl thienamycin (N-F-thienamycin), cefotaxime, moxalactam, and cefsulodin were tested by agar dilution against 125 isolates of Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, and Providencia stuartii. Against gentamicin-susceptible P. aeruginosa, N-F-thienamycin and cefsulodin were most active. Only N-F-thienamycin inhibited gentamicin-resistant P. aeruginosa at less than or equal to 4 microgram/ml. N-F-thienamycin's activity equaled or surpassed that of the other antibiotics tested against both the gentamicin-susceptible and -resistant Enterobacteriaceae.

Ceforanide kinetics in renal insufficiency.

Ceforanide (500 mg) was infused intravenously over 30 min into six normal subjects, 10 nondialysis patients with renal insufficiency, and six hemodialysis patients. Dialysis patients received two ceforanide infusions, one immediately before dialysis and another during an interdialysis period. Sequential plasma samples over 24 to 72 hr were assayed for ceforanide. Peak ceforanide levels (mean = 69 +/- 12 micrograms/ml) and volumes of distribution did not vary with creatinine clearance (Clcr, ml/min/1.73 m2) and both plasma clearance and renal clearance decreased linearly as Clcr decreased. Mean nonrenal clearance (4.6 +/- 1.8 ml/min/1.73 m2) did not vary with Clcr. Mean half-life was 3 hr in the normal subjects, increasing to approximately 25 hr in patients with severe renal insufficiency. Hemodialysis resulted in a removal of approximately 21% of the dose of ceforanide. Dosing recommendations for patients with renal insufficiency are provided.

Progressive disseminated histoplasmosis; favorable response to ketoconazole.

Four patients with disseminated histoplasmosis, two of whom had late relapses after previous therapy with amphotericin B, were treated with ketoconazole 200 to 400 mg daily for 1 year. All patients improved markedly during therapy, with resolution of symptoms decreasing liver and spleen size, and weight gain; resolution of oral ulcers occurred in the two patients in whom they were present. Decrease in serum alkaline phosphatase levels correlated well with clinical improvement. One patient who was much improved while receiving ketoconazole continued to harbor Histoplasma capsulatum in an abdominal aortic aneurysm, which became symptomatic 4 months after cessation of the drug. He underwent aneurysmectomy, and H. capsulatum isolated from the resected aneurysm was susceptible in vitro to ketoconazole. No significant adverse reactions to the drug were noted despite prolonged therapy. Our results indicate that ketoconazole may have a role in the therapy of disseminated histoplasmosis in adults.